The calciferols were the first class of hormonally active steroids to oe discovered and also the first for which subjects with hormone resistance could be identified. With recognition that vitamin D is the precursor for 1,25-dihydroxyvitamin D, it has become possible to characterize defects in the activation (1- hydroxylation) of vitamin D and defects in the target action of activated (1,25-dihydroxy) vitamin D. We have demonstrated a broad spectrum of manifestations of hereditary resistance to 1,25(0H)2D ranging from infantile rickets with alopecia and no intestinal response to calciferols to adult onset osteomalacia with satisfactory intestinal response to high doses of calciferols and with no epidermal abnormalities. Alopecia is found only in cases with the most severe grades of resistance to 1,25(0H)2D. This finding implicates the 1,25(0H)2D receptor, for the first time, in normal function of a tissue (hair follicle) outside the classical target in duodenal mucosa. A similar disorder has been recognized in new world monkeys. Cultured skin fibroblasts display many components of the 1,25(0H)2D effector system. Skin fibroblasts from all subjects with hereditary resistance to 1,25(0H)2D display abnormalities in this effector system, and defects in many discrete steps of this pathway have been identified with these cells. Other cells, such as bone cells, lymphocytes, and parathyroid cells can also be used to evalute actions of 1,25(0H)2D in vitro. Cells with mutations in the 1,25(0H)2D effector pathway can be used to explore mechanisms of calciferol action. They have been used to establish that the 1,25(0H)2D receptor mediates an extremely rapid (1-3 minutes) rise of cyclic GMP in response to 1,25(0H)2D3.